Infection of a target cell by human immunodeficiency virus type 1 (HIV-1) involves interaction with the CD4 receptor, reverse transcription of viral nucleic acids and transport of viral cDNA to the host cell nucleus where integration occurs. Reverse transcription of viral nucleic acids and transport of viral nucleic acids from the site of virus entry to the nucleus occurs within the context of a high molecular weight nucleoprotein complex. One component of the nucleoprotein reverse transcription complex, namely the gag matrix (MA) protein, plays a central role in the transport of this complex from the site of virus entry to the host cell nucleus. In addition to its nuclear import function during virus infection, gag MA is myristylated; a modification which is necessary from membrane targeting of gag precursors during virus assembly. We have recently demonstrated that phosphorylation of gag MA both on tyrosine and on serine regulates its opposing nuclear import and membrane targeting functions. Inhibitors of tyrosine or serine kinase activity markedly attenuate HIV-1 infectivity by preventing membrane dissociation of this complex at the site of virus entry. Thus, cellular kinases are required for optimal HIV-1 infectivity. The object of this NCDDG-HIV proposal is to evaluate whether kinases which mediate phosphorylation of gag MA constitute a cellular target for intervention of HIV-1 infectivity. Studies to be undertaken by the research components of the NCDDG include: 1. Provide biochemical and virological support for efforts to clone kinases which act on gag MA and for efforts to identify specific inhibitors of these kinases. 2. Through targeted screening, identify agents which inhibit the activity of kinases involved in HIV-1 gag MA phosphorylation and which, as a consequence, block HIV-1 infectivity. 3. Utilize biochemical and genetic approaches to identify and clone kinases involved in phosphorylation of gag MA. It is anticipated that these studies will lead to the derivation of novel agents for athe treatment of HIV-1 infection.